Malignant gliomas represent the single most costly and morbid neoplasm per capita. The prognosis for patients with these tumors has been largely unchanged by advances in surgery, radiation therapy and drug design. Our proposal provides an integrated effort to translate to clinical human trials laboratory advances in the design of herpes virus (HSV) vectors for the delivery of drug-enhancing genes to tumor cells. These effects build on achievements including over 35 publications over the past 2.5 years, the conduct of a human retroviral "gene-marking trial" and the design of three human therapeutic trials Four Projects and four Cores are united , in collaboration with GMP vector facilities, as a resource for the brain-tumor Consortium (NABTT) to provide gene therapies of glioblastomas. Our studies explore vascular and migratory cell delivery systems (Project 4- Breakfield) of herpes virus and herpes-based amplicon vector systems. Studies are designed to provide high titers of HSV vector containing enzymes and herpes-based amplicon vector systems. Studies are designed to provide high titers of HSV vector containing enzymes which separately and in synergy activate pro-drugs including cyclophosphamide and irinotecan. Initial toxicity studies in Aoutus and Scientific Advisory meetings have resulted in the addition of two new scientific aims: We will track the delivery of vector, transgene and delivery cells using novel radiolabels in rodents and we will evaluate the Cytotoxic T Lymphocyte response to novel tumor antigens B-gal and OVA as distinguished from herpes vectors. In Aoutus and Human Trials we will distinguish from herpes vectors. In Aoutus and Human trials we will examine the local CTL responses that follow herpes vector transduction into brain. Human and in-vitro drug studies will be supported by for manufacture of polymeric pro-drug systems, and analysis and modeling for single and multiple activated drugs. All studies will be supported by histologic and immunohistochemical evaluations of gene expression and changes in tumor and surrounding brain, as well as the molecular characterization of tumors. Our program defines a rational and scientific means to evaluate and expand the potential of gen therapy for brain tumors.